The goal of this project is to determine the role of the aryl hydrocarbon hydroxylase (AHH) system in mouse skin tumorigenesis by methylated and non-methylated polycyclic hydrocarbons. Pursuant to this goal, we will examine the effects of some modifiers of tumorigenesis on 7,12-dimethylbenz(a)anthracene, (DMBA), 3-methylcholanthrene (MC), benzo(a)pyrene (BP) and dibenz(a,h)anthracene (DBA) mouse skin tumorigenesis and metabolism. We shall determine the effects of 7,8- benzoflavone, 5,6-benzoflavone, phenobarbital, butylated hydroxytoluene, and fluocinolone acetonide when administered to mice either topically or in the diet on the initiation of skin tumors by topical treatment of DMBA, MC, BP, and DBA. The conversion of radioactive DMBA, MC, BP and DBA to organic solvent-soluble metabolites rapidly and efficiently separated by high-pressure liquid-chromatography will be used as the overall assessment of the AHH activity instead of the commonly used conversion of BP to 3-OH-BP. The effects of the modifiers applied in vivo or added in vitro on the profile of metabolites from the above hydrocarbons as revealed by liquid chromatography analyses will be investigated. The effects of the modifying agents applied in vivo on the epoxidation and hydration reactions specifically will be determined as follows: 1) the NADPH-requiring, microsomal catalyzed in vitro covalent binding of radioactive DMBA, MC, BP and DBA to DNA in the presence of the potent epoxide hydrase inhibitor 1,1,1-trichoropropene 2,3-oxide will be determined (index of activation step?); 2) the activity of the epoxide hydrase enzyme(s) will be assayed by the in vitro conversion of K-region epoxides of DMBA, MC, BP and DBA to dihydrodiols which will be measured by high-pressure liquid chromatography analysis (index of detoxification step?). The results of this project should give us a better understanding on the role of specific metabolites of the above polycyclic hydrocarbons in skin carcinogenesis and may provide a rational approach to the chemoprophylaxis of environmental carcinogens.